A tumor necrosis factor (hereinafter abbreviated as TNF) is a peptide of 157 amino acids, having a molecular weight of about 17,000. TNF is one of cytokines produced by various cells including macrophages.
Although TNF had been at first found as a cytokine showing a cytotoxic effect on tumor, subsequent studies have revealed that the activities of TNF are various, and not only limited to tumor cells but also extended to many other normal cells. Examples of such TNF activities include suppression of the lipoprotein lipase activity in adipocytes, expression of HLA antigen on blood endothelial cells and fibroblasts, interleukin-1 formation by fibroblasts or macrophages, activation of cytotoxic macrophages, suppression of CFU, formation of colony stimulating factor by fibroblasts, endothelial cells or some tumor cells, inhibition of the synthesis of proteoglycans and stimulation of their resorption in cartilage, activation of neutrophils and generation of superoxide, formation of procoagulant factor by blood endothelial cells, proliferation of fibroblasts, change in membrane potential of skeletal muscle, interferon .beta..sub.2 production by fibroblasts, and injury of blood endothelial cells. In these days, TNF has thus been recognized to be a cytokine which are involved broadly in vital protection through inflammation and immune response (Ann. Rev. Immunol., 10, 411 (1992)).
On the other hand, it has been found that continuous or excessive formation of TNF rather results in vigorous actions on normal cells to cause various diseases. It is also reported that TNF is known as cachectin which induces cachexia in cancer or infectious diseases which causes catabolic acceleration of total metabolism to lead to extreme wasting (B. Beutler, D. Greenwald, J. D. Hulmes et al., Nature, 316, 552-554 (1985), Kawakami, M., SEIKAGAKU (Biochemistry), 59, 1244-1247 (1987)).
An anti-TNF antibody is considered to be effective also for a septic shock (Starnes, H. F. Jr., Pearce, M. K., Tewari, A., Yim, J. H., Zou, J-C., Abrams, J. S., J. Immunol., 145, 4185-4191 (1990), Beutler, B., Milsark, I. W., Cerami, A. C., Science, 229, 869-871 (1985), Hinshaw, L. B., Tekamp-Olson, P., Chang, A. C. K. et al., Circ. Shock, 30, 279-292 (1990)).
An increased level of TNF is also observed in the synovial fluid or blood from patients with rheumatoid arthritis (Tetta, C., Camussi, G., Modena, V., Vittorio, C. D., Baglioni, C., Ann. Rheum. Dis., 49, 665-667 (1990)).
In addition, it is reported that there are many other diseases wherein a TNF level increase in blood, e.g., Kawasaki disease (Matsubara, T., Furukawa, S., Yabuta, K., Clin. Immunol. Immunopathol., 56, 29-36 (1990)); ulcerative colitis (Murch, S., Walker-Smith, J. A., Arch. Dis. Child, 66, 561 (1991)); Beh.cedilla.et disease (Akoglu, T., Direskeneli, H., Yazici, H., Lawrence, R., J. Rheumatol., 17, 1107-1108 (1990)); systemic lupus erythematosus (SLE) (Maury, C. P. J., Teppo, A-M., Arthritis Rheum., 32, 146-150 (1989)); graft versus host disease (GvHD) (J. Exp. Med., 175, 405-413 (1992)); multiple organ failure (Kawakami, M., Hayata, K., Medical Immunology, 20, 615-620 (1990)); malaria (Grau, G. E., Fajardo, L. F., Piguet, P. F., et al., Science, 237, 1210-1212 (1987)); acquired immune deficiency syndrome (AIDS) (Kawakami, M., Hayata K., Medical Immunology, 20, 615-620 (1990)); meningitis (Waage, A., Halstensen, A., Espevik, T., Lancet, I, 355-357 (1987)); fuluminant hepatitis (Sugano, K., KANZO (Liver), 33, 213-218 (1992)); and inflammatory Bowel disease (Maeda, M., SHOKAKI-TO- MEN-EKI (Digestive Organ and Immunity), 22, 111-114 (1989)).
From the above publications, it is understood that excessive formation of TNF sometimes adversely affect the living body. Therefore, further investigations are desired to develop TNF inhibitors available for the treatment of these diseases.
Pentoxifylline having a methylxanthine skeleton is known as a compound showing an activity of inhibiting TNF. It is reported that this compound possesses an activity of preventing death in endotoxin-shocked mice, an activity of improving the sense of well-being or preventing a weight loss in severe pulmonary tuberculosis patients or cancer patients (Zabel, P., Schade, F. U., Schlaak, M., Immunobiol., 187, 447-463 (1993), Dezube, B. J., Pardee, A. B., et al., Cancer Immuno. Immunother., 36, 57-60 (1993)).
In addition, glucocorticoid, protease inhibitors, phospholipase A.sub.2 inhibitors, lipoxygenase inhibitors, PAF (platelet aggregating factor) antagonists, radical scavengers, prostaglandin F.sub.2 or I.sub.2 and anti-TNF antibody are heretofore known as compounds or factors for showing a TNF inhibitory activity.
In the future, the function of TNF in association with diseases will be made clearer, using these low molecular compounds or antibodies. However, these compounds are accompanied by side effects due to a wide variety of the pharmacological activities. Therefore, it is desired to develop highly safe compounds based on a novel mechanism.
The present invention provides a therapeutic drug for diseases which TNF would cause, due to its inhibition against TNF formation or secretion. Such diseases include cachexia, sepsis, multiple organ failure, rheumatoid arthritis, ulcerative colitis, Beh.cedilla.et disease, systenic lupus erythematosus (SLE), graft versus host disease (GvHD), malaria, acquired immune deficiency syndrome (AIDS), meningitis, fuluminant hepatitis, and inflammatory Bowel disease.
The compounds which are used as the active ingredient in the present invention are known and disclosed, with their syntheses or anti-inflammatory or analgesic use, in, e.g., Chem. Pharm. Bull., 29 (8), 2135-2156 (1981), Synthetic Communications, 10 (11), 805-811 (1980), Chem. Pharm. Bull., 26 (6), 1633-1651 (1978), Japanese Patent Application KOKAI Nos. 53-23997, 53-12893, 52-71483, 52-51379, 51-8287, 51-100098 and 47-14183, Arzneim-Forsch., 22 (11), 1958-1962 (1972), U.S. Pat. No. 3,305,553, etc. However, these publications are totally silent on the activity of inhibiting the formation or secretion of TNF in accordance with the present invention.